This invention relates to a parenteral form of administration of the thalidomide derivative 3-(1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione (EM 12) and to a method for its production. This form of administration can be used for the therapy of inflammatory and haematological-oncological diseases.
The excess formation of the proinflammatory cytokine TNF-.alpha. (tumour necrosis factor) and of interleukin (IL)-12 by phagocyte cells (e.g. monocytes) plays a central part in the pathogenesis of various inflammatory diseases (Trinchieri 1995, Ann. Rev. Immunol. 13: 251).
One approach to the treatment of these diseases is to deliberately suppress the formation of these proinflammatory cytokines by the administration of immunomodulating active ingredients, such as dexamethasone or thalidomide, or the thalidomide derivative EM 12, for example. Whereas corticoids such as dexamethasone exist in injectable forms, this has not hitherto been the case for the derivative EM 12, which has an inmmunomodulatory effect. A parenteral form of administration for thalidomide has been proposed in co-pending U.S. Pat. No. 6,124,322, the disclosure of which is incorporated herein by reference.
Thalidomide has proved to be superior to classical immunosuppressants for the treatment of severe aphthous stomatitis. Other examples of diseases in which thalidomide has been shown to exhibit good efficacy without resulting in general immunosuppression include cutaneous lupus erythematodes, pyoderma gangrenosum and urogenital ulcers in Bechet's syndrome, as well as ulcerations, in those infected with HIV, which do not differ histologically from aphthous ulcers and in which--as distinct from most HIV-associated mucocutaneous lesions--no microbial causative agents can be detected. As distinct from aphthous stomatitis, these lesions, which can also sometimes assume the size of major aphthae, can occur in the entire digestive tract, and when they are located in the pharyngeal cavity or the gullet they can make the ingestion of food difficult and can also make the ingestion of oral medication difficult due to the pain which they cause.
In severe cases of pharyngeal or oesophageal ulcers in which oral ingestion is made difficult or may even be impossible, and in cases of HIV-associated pathology in which severe symptoms of diaorrhea make oral ingestion unpredictable, parenteral administration provides a solution. However, the low solubility in water of thalidomide (Arch. Pharm. 321, 371 (1988)) constitutes an obstacle to the parenteral administration of this active ingredient. There has therefore been no lack of attempts aimed at the development of water-soluble forms of administration.
Water-soluble thalidomide derivatives, which exhibit a considerably higher solubility in water than that of thalidomide and which are suitable for parenteral administration, are known from DE 42 11 812.
Furthermore, thalidomide prodrugs have been proposed for parenteral administration which can be administered in water-soluble form within the physiological pH range and are toxicologically harmless (DE 196 13 976). It is disadvantageous that the production of both types of compounds mentioned above is more costly than the production of thalidomide.
The thalidomide derivative EM 12 exhibits similar disadvantageous properties to thalidomide as regards its solubility in an aqueous medium and its tendency to undergo spontaneous hydrolysis. It has been found that the production of aqueous solutions is not practicable, due to the tendency of EM 12 to undergo spontaneous hydrolysis.